Nitric oxide (NO) is a signaling molecule in a number of human cells. It also involves in many physiological and pathological processes in tumor biology, regulating tumor blood flow, vascular permeability and angiogenesis, controlling the growth, migration and invasion of cancer cells. (1. Lala P K, et al, Cancer Metastasis Rev. March; 1998 17(1):91-106; Lam-Himlin D. et al, Neurochem Int. December; 2006 49(8):764-768. Epub 2006 September 2012; Mocellin S, et al, Med Res Rev. May; 2007 27(3):317-352; Ridnour L A, et al, Proc Natl Acad Sci USA. Sept. 13; 2005 102(37):13147-13152. Epub 12005 September 13142; Wink D A, et al, Free Radic Biol Med. Apr. 15; 2003 34(8):951-954). Interference of NO signaling might be a promising strategy as a novel cancer treatment. Several studies used NO to alter blood flow and vascular permeability for increasing the efficiency of drug delivery to tumors; other studies used NO to induce tumor cell killing or increase the sensitivity of chemotherapy or radiotherapy (Matsukado K, et al, Neurosurgery. 1996; 39(1):125-133; Mitchell J B, et al, International Journal of Radiation Oncology Biology Physics. 1998; 42(4):795-798; Weyerbrock A, et al, J Neurosurg. 2003; 99(4):728-737; Weyerbrock A, et al, Neuro Oncol. February; 2011 13(2):203-211; Wink D A, et al, Nitric Oxide-Biology and Chemistry. 1997; 1(1):88-94).
JS-K, [O2-(2,4-dinitrophenyl) 1-[(4-ethoxycarbonyl)piperazin-1-yl]diazen-1-ium-1,2-diolate], CAS Reg. No. 205432-12-8, is a NO donor and contains a O2-aryl diazeniumdiolates (NONOates) structural motif. The 2,4-dinitrophenyl group of the prodrug JS-K can be removed by a reaction with glutathione (GSH) to generate NO, which is catalyzed by glutathione-S-transferases (GSTs). (Shami P J, et al. Mol Cancer Ther. 2003; 2(4):409-417). GSTs are overexpressed in many kinds of tumors. Especially in multiple myeloma cells, GSTs are overexpressed about 7-fold comparing to normal plasma cells. The higher concentration of GSTs in tumor cells catalyzes JS-K to generate higher intracellular concentration of NO, which results in cytotoxic activities. JS-K shows a concentration-dependent and high effective antiproliferative effect to leukemia (HL-60), prostate cancer (PPC-1), multiple myeloma (MM), hepatoma (Hep 3B), and lung cancer in vitro and in vivo (Shami P J, et al, Mol Cancer Ther. 2003; 2(4):409-417; Kiziltepe T, et al. Blood. Jul. 15; 2007 110(2):709-718. Epub 2007 March 2023; Liu J, et al, Mol Cancer Ther. 2004; 3(6):709-714; Maciag A E, et al, J Pharmacol Exp Ther. February; 2011 336(2):313-320; Ren Z, et al, J Cell Physiol. 2003; 197(3):426-434; Shami P J, et al, J Med Chem. Jul. 13; 2006 49(14):4356-4366; Udupi V, et al, Leuk Res. October; 2006 30(10):1279-1283. Epub 2006 January 1224).
The mechanisms of inducing cell death by JS-K includes arylation of GSH; activation of caspases-3, -8 and -9; induction of protein kinases p38, JNK and (MAPK) ERK; and other cellular nucleophiles (Ren Z, et al, J Cell Physiol. 2003; 197(3):426-434; Shami P J, et al, J Med Chem. Jul. 13; 2006 49(14):4356-4366). In leukemia cells, JS-K also induces mitochondrial cytochrome c release (Udupi V, et al, Leuk Res. October; 2006 30(10):1279-1283. Epub 2006 January 1224).
Bis O2-aryl diazeniumdiolate compounds with optimized properties may have increased efficacy in treating hyperproliferative disorders, including cancer. Therefore, there is a need for new compounds to treat cancer, especially pancreatic cancer.